The present invention relates to an improved process for the preparation of 1-Propyl-2,4,5-trimethoxybenzene of the formula I 
from the toxic compound xcex2-asarone of Acorus calamus or from crude calamus oil containing xcex2-asarone. The present invention also relates to a process for the preparation of 1-Propyl-2,4,5-trimethoxybenzene from toxic compound xcex2-asarone of Acorus calamus or from crude calamus oil containing xcex2-asarone and useful as a new kind of aroma molecule. The present invention also relates to a process for the preparation of salicylamide based antipsychotic drug from 1-Propyl-2, 4, 5-trimethoxybenzene, and other uses thereof.
xcex2-asarone (cis-2,4,5-trimethoxy-1-propenylbenzene) is found in a number of plants such as Orthodon calveriei Level and Acorus gramineus (Nguyen, X. D.; Ladinh, M, Vuviet, N.; Luudam, C. and Leclercq, P. A., J. of Essential Oil Research 7(1):111-112 (1995) and Perrett, S. and Whitfield, P. J., Phytotherapy Research 9(6):405-409 (1995)). Among all the plants, the highest percentage of xcex2-asarone is present in tetraploid and hexaploid varieties of Acorus calamus (Rost, L. C. M., Planta Medica 36:350 (1979); Srivastava, M., Saxena, A. and Baby, P., Orient. J. Chem., 13(1): 97-98 (1997); Tang, W. and Eisenbrand, G., Chinese Drugs of Plant Origin, Springer-verlag, New York, 45-46 (1992) and Kaul, M. K., Medicinal Plants of Kashmir and Ladakh, Indus Publishing Company, 92-93 (1997)).
Acorus calamus Linn, a member of the family of Araceae, commonly known as xe2x80x9csweet flagxe2x80x9d, is a perennial plant (Grieve, M., A Modern Herbal, Tiger Books International, London, 726-729 (1998)) that grows in the wild along swamps, brooks, rivers and lakes worldwide. The plant is also cultivated widely in India, Pakistan, Bangladesh, China, Japan, Poland, Hungary, Yugoslavia, Bulgaria, USSR, Holland, USA and several other countries because of its varied medicinal activities and the great demand for its essential oil in the flavour and perfumery industries, in alcoholic beverages and for its antibacterial, antifungal and insecticidal properties (Treben, M. Health Through God""s Pharmacy, Wilhelm Ennthaler, Steyer, Austria, 12-14 (1986); Akitar, H.; Virmani, O. P.; Popli, S. P., Misra, L. N., Gupta, M. M., Srivastava, G. N., Abraham, Z. and Singh, A. K., Dictionary of Indian Medicinal Plants, CIMAP, RSM Nagar, Lucknow, 10-11 (1992); Motley, T. J., Economic Botany, 48: 397-412 (1994) and Lawrence, B. M. and Reynolds, R. J., Perfumer and Flavorist 22(2):59-67 (1997)). However, photochemical reports on Acorus calamus reveals that the qualitative and quantitative composition of calamus oil and particularly the percentage of asarone is greatly affected by the location, growth stages and the species of Acorus calamus. A lot of discrepancy and variability has been noticed in asarone percentage of Asian and American calamus oil. It has been found that the oil of diploid plants (N. American) does not contain the carcinogenic compound xcex2-asarone at all. The triploid race (E. European) contains limited amount of xcex2-asarone varying from 3 to 8% and is therefore, usable in terms of both clinical effectiveness and safety (Stahl, E. and Keller, K., Planta Medica 43:128-140 (1981)). However, calamus oil originating from tetraploid or hexaploid varieties distributed extensively in Asian countries like India, Japan, Pakistan and China, contains a very high percentage of xcex2-asarone varying from 70 to 90% (Waltraud, G. and Schimmer, O., Mutation Research 121:191-194 (1983); Mazza, G., J. of Chromatography 328:179-206 (1985); Nigani, M. C.; Ateeque, A.; Misra, L. N. and Ahmad, A., Indian Perfumer 34: 282-285 (1990) and Bonaccorsi, I.; Cortroneo, A.; Chowdhury, J. U. and Yusuf, M., Essenze Derv. Agrum, 67(4): 392-402 (1997)). The higher percentage of xcex2-asarone is experimentally proved to be carcinogenic in animals and was found to induce tumours in the duodenal region after oral administration (Taylor, J. M.; Jones, W. I.; Hogan, E. C.; Gross, M. A.; David, D. A. and Cook, E. L., Toxicol. Appl. Pharmacol. 10:405 (1967); Keller, K.; Odenthal, K. P. and Leng, P. E., Planta Medica 1:6-9 (1985) and Riaz, M.; Shadab, Q.; Chaudhary, F. M., Hamdard Medicus 38(2); 50-62 (1995)). In addition, xcex2-asarone has also shown chromosome damaging effect on human lymphocytes in-vitro after metabolic activation (Abel, G., Planta Medica 53(3): 251-253 (1987)). As a result, the use of this well known medicinal plant which had been in use for many years, is now prohibited in flavour, perfumery and human food (Harborne, J. B. and Baxter, H., Phytochemical Dictionary: A Handbook of Bioactive Compounds from Plants, Taylor and Francis Ltd., Washington D.C., 474 (1993) and McGuffin, M., American Herbal Products Association""s Botanical Safety Handbook, CRC Press, Inc., Boca Raton Fla., USA, 231 (1997)).
The oil and extracts of Acorus calamus have been reported to have numerous pharmacological activities. Some of the active ingredients found therein are glucosides, sitosterol (Patra, A. and Mitra, A. K., Indian J. Chem., Sec B, 17B:412 (1979), amino acids, acoramone (Patra, A. and Mitra, A. K., J. of Natural Products 44(6):668-669 (1981), flavones, fatty acid, sesquiterpene named calamnonone (Wu, Li.; Xiang, T.; Liu, T., Li, M.; Gao, Z. and Meng, X., Bopuxue Zazhi 15 (3):249-251 (1998) and triterpenoid saponins (Rai, R., Siddiqui, I. R. and Singh, J., Indian J. Chem., Sec B, 37 B(5), 473-476 (1998)) Modern applications of the Acorus calamus plant include its use in cleansing of facial skin (Horste, B.; Sarma, I.; Gercikovs, I. and Gordejeva, V., L. V. Patent No. 92-920022, issued May 28, (1992); germination inhibitors (Nawamaki, K. and Kuroyanagi, M., Phytochenistry 43 (6):1175-1182, (1996); in formulation for alcoholic bitters (Sargunas, G.; Daniuniene, G.; Talacka, C.; and Aleksiunas S., L. T. Patent No. 36793, issued Jan. 25, (1996) and for the prevention and improvement of vision disorders (Mihara, T., JP Patent No. 10324636 A2, issued Dec. 8, (1998)).
Acorus calamus, known as xe2x80x9cvaichxe2x80x9d in Hindi, has also been credited with many medicinal properties from ancient ties in Ayurvedic system of India (Vohora, S. B.; Shah, S. A. and Dandiya, P. C., J. of Ethnopharmacology 28(1): 53-62 (1990); Rastogi, R. P. and Mehrotra, B. N., Compendium of Indian Medicinal Plants, 1:1, (1990), C. S. I. R., New Delhi and Asolkar, L. V., Kakkar, K. K. and Chakre, O. J., Glossary of Indian Medicinal Plants with Active Principles, Publications and Information Directorate (C. S. I. R), New Delhi, Part-I, 18-20 (1992)). It is known for more than 2000 years in China for treating a number of disorders (Albert, Y. L., Encyclopaedia of Common Natural Ingredient Used in Food, Drugs and Cosmetics, ed, John Wiley and Sons Inc. New York, 111-112 (1996)). However, all the above uses and medicinal potential of Acorus calamus have been hampered because of carcinogenic effect of xcex2-asarone (Opdyke, D. L. J., Food Cosmet. Toxicol., 15: 623, (1997)). xcex1-Asarone is also reported to be fatal in rats (Lopez, M. L.; Hernandez, A.; Chamorro, G. and Mendoza, F. T., Planta Medica 59(20):115-120 (1993) and Chamorro, G., Salazar, M., Salazar, S. and Mendoza, T., Revista-de-Investigation-Clinica 45(6):597-604 (1993)). As a result, countries such as India, Pakistan, Bangladesh, Japan and China where plants of tetraploid and hexaploid origin contain 70 to 90% xcex2-asarone are most affected by the prohibition on the use of calamus oil.
The levels of xcex2-asarone can be easily detected by IR-spectroscopy (Stahl, E. and Keller, K, Pharmazie 36(1):53-57 (1981); HPTLC (Narayana, D. B. A.; Raghuvanshi, P; Agarwal, S. and Srinivas, K. S., Indian Drugs 32(6):254-257 (1995); densitometry (Tamas, M.; Oprean, R. and Roman, L., Farmacia (Bucharest) 44 (5-6): 13-21 (1996)); gas chromatography (Baxter, R. M.; Dandiya, P. C.; Kandel, S. I.; Okanya, A. and Walker, G. C., Nature 185:466-467 (1960) and Spilkova, J. T.; Tomasch, J.; Vavra R. and Dusek, J, Ceska Slov. Farm., 45 (3): 146-148 (1996)) and GC-MS (Oprean, R.; Tamas, M. and Roman, L., J Pharm. Biomed. Anal., 18 (1,2): 227-234 (1998)).
Separation of xcex2-asarone from calamus rhizomes (americanus var.) by supercritical extraction (Stahl, E. and Keller, K., Planta Medica 47 (2): 75-78 (1983)) or by raising plants on alkaline soil (Chowdhary, A. R.; Gupta, R. C. and Sharma, M. C., Indian Perfumer 41 (4): 154-156 (1997)) have been developed. However, these methods do not effectively lower the high percentage (70 to 90%) of asarone content of tetraploid or hexaploid varieties. It is therefore imperative to provide a simple chemical process by which xcex2-asarone or crude calamus oil can be easily modified to reduce its carcinogenic effect rather than by reduction in the percentage of asarones by any other means. While supercritical gas extraction of calamus oil (americanus variety) with fractionated separation has been reported (Keller, K. and Stahl, E., Planta Medica 47(2): 71-74 (1983)) to make xcex2-asarone free calamus oil, fractionation will not be cost effective with tetraploid or hexaploid varieties having very high percentage of xcex2-asarone (70 to 90%).
Interest in development of a simple and economical chemical process to reduce the toxicity of carcinogenic compound xcex2-asarone by elimination of side double bond continues to be strong as evidenced by numerous literature reports that show that the double bond of asarone is responsible for bioactivity and photooxidation. A detailed literature survey reveals that calamus oil has been found active as antigonadal, antifeedant and growth inhibitory in insects. The activities of calamus oil are found due to the presence of double bond in the alkyl side chain and cis configuration of xcex2-asarone (Saxena, B. P.; Koul, O.; Tikku, K.; Atal, C. K. and Opender, K., Nature, London, 270(5637): 512-513 (1977); Koul, O., Sci. Acad. Medal Lectures, Ed. INSA, New Delhi, India, 62 (1979) and Koul, O.; Smirle, M. J. and Isman, M. B., J. Chem. Ecol. 16:1911-1920 (1990)). The side double bond forms asarone epoxide and asarone diol which is identified in the insect excreta of Peridroma saucia larvae (Noctuidae: Lepidoptera) (Koul, O.; Smirle, M. J.; Isman, M. B. and Szeto, Y. S., Experientia 46:1082-1084 (1990)). The double bond of xcex2-asarone is also found to be photosensitive and while standing the calamus oil on long storage without exclusion of air and light, the oil got contaminated with photo-oxidised products such as asaraldehyde and dimer (Saxena, D. B. and Mukerjee, S. K., Indian J. Chemistry, Sec B, 24 B: 683-684 (1985)), Recently, a number of photoxidised product formations were also studied by light induced transformation of xcex2-asarone in ethanolic solutions (Lander, V. and Schreier, P., Flavour Fragrance J. 6(1) 21-28 (1991)). Based on the above survey, it appears logical to develop a convenient chemical process for utilising the side double bond of xcex2-asarone to reduce its toxicity.
It is reported that the side double bond of isolated xcex2-asarone of Acorus calamus or crude calamus oil is reduced either over Pd, Pt, Pd(OH)2, PtO2, BaSO4/Pd, Raney nickel and ammonium formate to obtain 1-Propyl-2,4,5-trimethoxybenzene with improved properties such as an aroma that is better than the pungent smell of xcex2-asarone (Joseph G. C.; Clare, D T.; John, P. L., Ranbir, K. B.; Paul, L. and Jan, R. F., J. Med. Chem. 32:2210:2214 (1989); Christopher, I., Fincham, M. H.; David, R. H.; David, C. H., John, C. O.; Giles, S. R.; David, C. R. and Edward, R., J. Med. Chem. 35:1472-1484 (1992) and Tomoyuki, Y.; Ryo, N., Toru, K.; Shinichi, T.; Tamako, N.; Tokio, Y. and Toshiyasu, M., J. Med. Chem. 40:1252-1257 (1997)).
The reaction schemes of the processes are given below: 
The olfactory assessment of 1-Propyl-2,4,5-trimethoxybenzene is performed as per Indian standard of 2284, 1997 (Bureau of Indian Standard, Manaki Bhavan, 9 Bahadur Shah Zafar Marg, New Delhi). The odour effect perceived by the olfactory nerves on smelling a strip impregnated with an oil is revealed as sweet, ylang, slightly spicy and fruity thereby enabling use as multipurpose additives in the areas of mouthwash, tooth paste, antiseptic soap products, chewing gum flavour and little in spicy products. In addition, it was observed that the product 1-Propyl-2,4,5-trimethoxybenzene is a simple and an economical starting material for synthesis of salicylamide based antipsychotic drugs (5,6-dimethoxy-N[(1-ethyl-2-pyrrolidinyl)methyl]-3-propylsalicylamide).
The salicylamide derivative displays high and stereoselective affinity for the [3H] spiperone and [3H] raclopride binding sites in vitro (dePaulis, T.; Kumar, Y., Johansson, L; Ramsby, S.; Florvall, L; Hall, H.; Angeby, M. K. and Ogren, S O., J. Med. Chem 28, 1263-1269(1985) and dePaulis, T.; Kumar, Y.; Johansson, L., Ramsby, S.; Hall, H.; Sallemark, M; Angeby, M. K. and Ogren, S. O., J. Med. Chem. 29:61-69 (1986)). Recently, Hogberg T., Stefan, B.; Tomas, D. P.; Lars, J.; Peter, S; Hakan, H. and Ogren, S. O., J. Med. Chem. 33 1155-1163 (1990) have synthesized a series of 3-substituted salicylamide derivatives in which the presence of 3-propyl group and 5,6-dimethoxy group at salicylamide ring shows a very high and stereoselective affinity for the dopamine-D2 receptor. However, the reported synthesis for salicylamide derivative involved several steps in which intermediate 1-Propyl-2,4,5-trimethoxybenzene is itself synthesized in two steps by Friedel-Craft acylation of an expensive material 1,2,4-trimethoxybenzene with propylchloride followed by catalytic hydrogenation with an overall in lower yield (reaction scheme given below as Scheme III). 
The main object of the present invention is to develop a process for the preparation of 1-propyl-2,4,5-trimethoxybenzene from high toxic compound xcex2-asarone present in the asarone bearing varieties of Acorus calamus or from crude calamus oil containing xcex2-asarone obtained therein.
It is another object of the invention to develop a process for the preparation of 1-propyl-2,4,5-trimethoxybenzene which is useful as a new kind of aroma molecule with multifarious applications.
It is another object of the invention to develop a process for the preparation of 1-propyl-2,4,5-trimethoxybenzene which is useful as a starting material for salicylamide based antipsychotic drugs.
Another object of the present invention is to provide a simple process for isolation of xcex2-asarone in high purity from Acorus calamus oil.
Still another object of the present invention is to provide a simple process for the preparation of 1-Propyl-2,4,5-trimethoxybenzene by catalytic reduction of above isolated xcex2-asarone.
Yet another object of the present invention is to provide a simple and an inexpensive process for the preparation of 1-Propyl-2,4,5-trimethoxybenzene by direct reduction of calamus oil in which the percentage of asarones (including xcex1, xcex2 and xcex3-asarone) go upto 90% in tetraploid or hexaploid varieties of Acorus calamus oil.
Yet another object of the present invention is to provide 1-Propyl-2,4,5-trimethoxybenzene as an inexpensive and simple starting material for synthesis of several drugs, for example salicylamide based antipsychotic drugs.
Yet another object of the present invention is to eliminate or minimize the toxicity of calamus oil of tetraploid or hexaploid varieties of Asian countries, thereby enhancing the profitable use thereof.
Yet another object of the present invention is to provide a simple reduction process in converting essential oils of other asarones rich plants such as Asarium europaeum, Crowea angustifolia and Heterotropa yakusimensis into useful products such as 1-Propyl-2,4,5-trimethoxybenzene for use in the flavour, perfumery and pharmaceutical industries.
Accordingly, the present invention relates to a process for the preparation of 1-Propyl-2,4,5-trimethoxybenzene of the formula I useful as a aroma molecule and as a starting material and intermediate for preparation of various drugs. 
the said process comprising the steps of
(a) providing crude calamus oil or xcex2-asarone in a solvent selected from the group consisting of ethanol, methanol, THF, DCM, Toluene and chloroform
(b) hydrogenation of the solution in the presence of a catalyst selected from the group comprising of Pd/C, Pt, Pd(OH)2, Raney nickel and ammonium formate at a pressure in the range of 10-40 psi hydrogen gas and at a temperature in the range of 15-40xc2x0 C.;
(c) filtering the catalyst and removing the solvent under reduced pressure in the range of 10-100 mm Hg;
(d) subjecting the reduced calamus oil to column or silica gel chromatography using an eluent to obtain the desired product in liquid form with 85-97% purity.
In one embodiment of the invention the catalyst comprises 5-10% Pd/C.
In another embodiment of the invention, the calamus oil used is of tetraploid or hexaploid origin.
In yet another embodiment of the invention, a new kind of honey and rose aroma is detected in the case of reduced calamus oil.
In yet another embodiment of the invention, a new kind of sweet, ylang, slightly spicy and fruity aroma is detected in case of 1-Propyl-2,4,5-trimethoxybenzene.
In another embodiment of the invention, the reduced calamus oil is useful in the toiletry soap, shaving cream and tobacco products.
In another embodiment, the invention relates to the use of 1-Propyl-2,4,5-trimethoxybenzene as a multipurpose additive in mouthwash, tooth paste, antiseptic soap products, chewing gum flavour and in spicy products.
In a further embodiment, the invention relates to the use of 1-Propyl-2,4,5-trimethoxybenzene as an inexpensive and simple starting material for the preparation of the 3-propyl-5,6-dimethoxysalicylamide based antipsychotic drug 5,6-dimethoxy-N[(1-ethyl-2-pyrrolidinyl)methyl]-3-propylsalicylamide.
In another embodiment, the invention relates to the conversion of 1-Propyl-2,4,5-trimethoxybenzene to products which can be used for flavour, perfumery industries and as starting material for various important drugs and for new organic compounds by bromination, oxidation, reduction, coupling reaction, allylic hydroxylation, dimerisation, formylation, Grignard reaction, oxymercuration-demercuration, demethylation, alkylation and epoxidation.
In a further embodiment of the invention, the crude calamus oil is extracted front asarone rich plants such as Asarum europaeum, Crowea angustifolia and Heterotropa yakusimensis. 
In another embodiment of the invention, the toxicity of the reduced calamus oil is two times less than that of the starting crude calamus oil.
In another embodiment of the present invention a simple catalytic hydrogenation of either xcex2-asarone of Acorus calamus or calamus oil is described to obtain 1-Propyl-2,4,5-trimethoxybenzene or reduced calamus oil with a new kind of sweet, fruity, spicy and honey and rosy aroma for use flavour, perfumery and pharmaceutical industries.
In yet another embodiment of the present invention a simple catalytic process is described to convert other asarones rich plants such as Asarum europaeum, Crowea angustifolia and Heterotropa yakusimensis into useful products such as 1-Propyl-2,4,5-trimethoxybenzene for various applications.